We propose to validate approaches using a novel portable X-ray fluorescence (XRF) device for the in vivo analysis of metals in humans. Concentrations of lead (Pb) in bone and several metals in toenails are currently used to assess long-term exposures to these metals in epidemiological health research. While these biomarkers provide valuable exposure data that has proved extremely useful in many health studies of metal exposure, they have drawbacks that can limit their utility and possibly bias results obtained. Chief among these is acceptability to research study subjects, which can limit the number of participants, and as a result reduce the power to detect associations (and in some cases make studies completely unfeasible) and potentially bias results depending on who agrees to participate. The conventional approach to bone Pb analyses-Cd109 KXRF-requires participants to come to a central study site and sit still for at least one half hour. This can be burden to many, and for some patient populations, e.g. patients with dementia, make a study essentially impossible. In addition, regulatory requirements around the use of the radioactive Cd109 source have limited the number of research groups with this capability. Measuring metals in toenails requires that study subjects have sufficient toenail length to obtain clippings, which can limit participation, but furthermore, some populations find providing toenail clippings unacceptable, making research among them impossible. Our new approach involves measurements with a portable XRF device and can be done in a matter of minutes, non-invasively on intact tissue. These advantages will obviate the problems with the current conventional approaches, thereby resulting in a tremendous expansion of research into health effects of metal exposures, opening up the possibility of human health research on metals at sites of particular need, and helping direct public health exposure prevention efforts related to metal exposures by providing real-time on-site diagnosis of metal intoxication. In the initial phase of our study, we will compare the analysis of Pb in bone and mercury (Hg) and manganese (Mn) in toenails with the current state-of-the-art measurement approaches. Contingent on our new approach meeting validation and feasibility criteria, we will evaluate exposures to these three metals in relation to cognitive decline within the context of a large, established population-based research cohort of ethnically diverse elderly adults, the Chicago Health and Aging Project. We will compare findings using the XRF-based measurement of bone Pb with Pb exposure based on occupational history, a commonly available, though far from ideal, source of long-term exposure data in large studies of adults.